RET positive

Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC.

P=N/A, N=25, Not yet recruiting, Fudan University

RET fusion-positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET tend to occur at earlier stages, whereas non-KIF5B are more frequently associated with CDKN2A co-mutations and may derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion-positive LUAD.

Herein, we present a clinical case of a patient with stage IIIA RET fusion-positive adenocarcinoma who received neoadjuvant nivolumab immunotherapy combined with nab-paclitaxel and carboplatin chemotherapy followed by surgery. The postoperative pathologic results revealed pathological complete response (pCR) and no residual viable tumor cells were observed in lymph nodes. This case validates the clinical activity of immunotherapy-chemotherapy in the neoadjuvant setting, providing a foundation for continued exploration in the treatment of early-stage RET fusion-positive NSCLC.

These findings provide new insights into the individualized treatment of RET + NSCLC patients and emphasize the importance of considering the overall health status of patients in treatment decisions.

Real-world data showed selpercatinib to be effective in patients with RET fusion-positive NSCLC in Japan, with a favorable safety profile and no new safety concerns.

We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

This case suggests that selpercatinib rechallenge may be effective in difficult-to-treat RET-positive NSCLC patients, including those with uncontrolled CNS disease.

Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.

Selpercatinib was discontinued, and treatment with intravenous hydration, febuxostat, and furosemide was initiated. This case highlights that potent targeted therapy can trigger TLS even in the absence of conventional risk factors. Early recognition and aggressive management are essential to mitigate risk and allow continuation of effective treatment.